Abstract
Intrinsic functional connectivity of large-scale brain networks has been shown to change with aging and Alzheimer’s disease (AD). These alterations are thought to reflect changes in synaptic function, but the underlying biological mechanisms are poorly understood. This study examined whether Neuronal Pentraxin 2 (NPTX2), a synaptic protein that mediates homeostatic strengthening of inhibitory circuits to control cortical excitability, is associated with functional connectivity as measured by resting-state functional magnetic resonance imaging (rsfMRI) in five large-scale cognitive brain networks. In this cross-sectional study, rsfMRI scans were obtained from 130 older individuals (mean age = 69 years) with normal cognition (N = 113) and Mild Cognitive Impairment (N = 17); NPTX2 was measured in the same individuals in cerebrospinal fluid (CSF). Higher levels of NPTX2 in CSF were associated with greater functional connectivity in the salience/ventral attention network, based on linear regression analysis. Moreover, this association was stronger among individuals with lower levels of cognitive reserve, as measured by a composite score (comprised of years of education, reading, and vocabulary measures). Additionally, higher connectivity in the salience/ventral attention network was related to better performance on a composite measure of executive function. Levels of NPTX2 were not associated with connectivity in other networks (executive control, limbic, dorsal attention, and default-mode). Findings also confirmed prior reports that individuals with MCI have lower levels of NPTX2 compared to those with normal cognition. Taken together, the results suggest that NPTX2 mechanisms may play a central role among older individuals in connectivity within the salience/ventral attention network and for cognitive tasks that require modulation of attention and response selection.
Highlights
It is increasingly recognized that aging and Alzheimer’s disease (AD) are accompanied by alterations in functional connectivity in large-scale brain networks, as measured by resting-state functional magnetic resonance imaging (e.g., Betzel et al, 2014; Dennis and Thompson, 2014; Badhwar et al, 2017)
The findings that both Neuronal Pentraxin 2 (NPTX2) and functional connectivity measured by resting-state functional magnetic resonance imaging (rsfMRI) are linked to intrinsic brain rhythmicity and both change with aging and AD, suggests that levels of NPTX2 in cerebrospinal fluid (CSF) may be related to functional connectivity in large-scale brain networks
This study investigated the relationship between CSF levels of NPTX2, a synaptic protein that regulates synaptic plasticity and rhythmicity in cortical circuits, and resting-state functional connectivity in 5 intrinsically organized large-scale brain networks among a group of older individuals consisting of participants with normal cognition and subjects with Mild Cognitive Impairment (MCI)
Summary
It is increasingly recognized that aging and Alzheimer’s disease (AD) are accompanied by alterations in functional connectivity in large-scale brain networks, as measured by resting-state functional magnetic resonance imaging (rsfMRI) (e.g., Betzel et al, 2014; Dennis and Thompson, 2014; Badhwar et al, 2017). A recent meta-analysis reported that functional connectivity as measured by rsfMRI differs among patients with AD dementia compared to those with normal cognition in three specific networks: the default-mode network, the salience/ventral attention network, and the limbic network (Badhwar et al, 2017). CSF levels of NPTX2 are reduced in patients with AD dementia and MCI, compared to controls and correlate with cognitive performance (Xiao et al, 2017) The findings that both NPTX2 and functional connectivity measured by rsfMRI are linked to intrinsic brain rhythmicity and both change with aging and AD, suggests that levels of NPTX2 in CSF may be related to functional connectivity in large-scale brain networks. We explored whether the association between NPTX2 and diagnostic status (i.e., cognitively normal, MCI) differed as a function of age, APOE e4 carrier status, and level of CR
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